Intermolecular dearomative C2-arylation of N-Ac indoles activated by FeCl3

Article abstract of DOI:10.1039/c6cc01654e

We report the FeCl₃-mediated direct addition of electron-rich arenes to the C2-position of electrophilic N-Ac indoles under mild conditions (room temperature, air). No functional group is required on the arene nucleophile: one of its C-H bonds is added to the C2=C3 double bond of the indole nucleus in a Friedel-Crafts-type reaction. This dearomatisation process delivered a broad range of C2-arylated indolines.

Full text of DOI:10.1039/c6cc01654e

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DOI: 10.1039/C6CC01654E
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COMMUNICATION
Intermolecular Dearomative C2-Arylation of N-Ac Indoles
Activated by FeCl3
Raj Kumar Nandi,a Friederike Ratsch,a Rodolphe Beaud,a Régis Guillot,a Cyrille Kouklovskya and
Received 00th January 20xx,
Accepted 00th January 20xx
Guillaume Vincenta*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report the FeCl3-mediated direct addition of electron-rich The arylative dearomatisation of indoles also allows to
arenes to the C2-position of electrophilic N-Ac indoles in mild transform a flat heterocycle into a 3-D structure which is more
conditions (room temperature, air). No functional group is required poised to explore chemical space in the context of drug
on the arene nucleophile: one of its C-H bond is added to the C2=C3 discovery.8
double bond of the indole nucleus in a Friedel-Crafts-type reaction. Indoles 1 are widely known to be highly nucleophilic at the C3-
This dearomatisation process delivered a broad range of C2- position leading in presence of electrophiles or acid to indolium
arylated indolines.
ions 2 which can be trapped by nucleophiles at the C2-position
and delivered functionalized indolines 3, usually in the
intramolecular mode (Scheme 1).9 Due to the propensity of
indolium ions 2 to form dimeric compounds via attack of indole
1 at C2,10 intermolecular addition of aryl nucleophiles to
indoliums such as 2 are very rare.11 Only few nucleophiles such
as allyboranes or hydrides could be added to 2 in the
intermolecular mode.12
The functionalization of indoles derivatives via dearomatisation
reactions is a field of intense synthetic efforts due to the
biological relevance of the heterocyclic scaffolds obtained.1 In
this context, we have recently described several methods for
the dearomative C3-arylation of indoles2 via FeCl3-activation of
3-substituted N-Ac indoles3 or oxidation of indoles with NIS4 or
from N-hydroxyindoles5 using the electrophilicity of indoles.6
Our next goal was to achieve the related C2-arylation of indoles
due to the presence of the C2-arylindoline motif in several
natural products such as phalarine, hinckdentine
tabernaebovine (Figure 1).7
A or
Scheme 1. Innate reactivity of the indole nucleus.
Usually, the C2-arylative dearomatisation of indoles rely on
intramolecular reactions with the aryl substituent attached to
the nitrogen of the indole nucleus. In that cases, the aryl group
is introduced by transformation of an aryl-halogen bond via
palladium-catalysed13 or radical reactions.14
Figure 1. C2-arylindoline-containing natural products.
In the intermolecular mode, the C2-arylation of indoles could
take place by the 1,4 addition of Grignard reagents to indoles
containing a strong electronwithdrawing group at C3.15 An
elegant
palladium-catalyzed
3-oxy-2-arylation
of 3-
a. Univ Paris Sud, CNRS, Université Paris-Saclay
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO)
Equipe Méthodologie, Synthèse et Molécules Thérapeutiques (MS&MT)
91405, Orsay (France)
unsubstituted indoles with phenylboronic acids and TEMPO was
described.16 These methods rely on the use of a functional
group on the aromatic nucleophile. Alternatively, during the
total synthesis of dideepoxytabernaebovine,
straightforward addition of electron rich arenes to an indolium
E-mail: guillaume.vincent@u-psud.fr
Electronic Supplementary Information (ESI) available: [experimental procedures,
characterisation and NMR spectra of new compounds and X-ray data See
DOI: 10.1039/x0xx00000x
a rare and
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intermediate such as 2 was deployed.11a A formal [4+2] partners for the regioselective C2-hydroarylation leading to 8f-
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DOI: 10.1039/C6CC01654E
cycloaddition with a N-phenyl iminium intermediate was also h in 60-47% yields (entries 6-8). Fluorine-containing arene 5i
described.17 We achieved the 3-oxy-2-arylation of indoles also delivered 8i in 57% yields (entries 9). Finally, less electron
during the DDQ-mediated oxidative coupling between phenols rich arenes 5j,k surprisingly delivered moderate yields of 3-
and 3-substituted N-Ac-indoles activated by FeCl3.18
arylated indolines 6j,k (entries 10, 11). It seems that the
Despite these achievements, we felt like that a general method regioselectivity of the hydroarylation is also dependant of the
for the C2-arylation of indoles from the functionalization of the arene nucleophile. The rational for this observation is,
C-H bond of the aromatic nucleophile was lacking. To achieve presently, unclear to us.
the C2-regioselective addition of a C-H bond across the C2=C3
Table 1. Scope of aromatic nucleophiles 5.
double bond of indoles, our experience in the activation of N-
Ac-indoles by FeCl3 was crucial to induce a Friedel-Crafts
process.3 We discovered that the FeCl3-mediated
hydroarylation of 3-unsubstituted N-Ac-indoles, proceeds at the
C2-position. We can postulate that the complexation of FeCl3 by
the oxygen of the acetyl lead to the sequestration of the
nitrogen lone pair by conjugation, the C2=C3 bond could then
Entry
Arene 5
Product
Yielda
be activated by an acid species and formally lead to a positive
charge at C2 or C3.3b If a substituent is present at C3, the positive
charge could be more stabilized at C3 by the formation of a
tertiary benzylic carbocation.3a,b If the C3 position lacks
substitution, the resulting secondary benzylic carbocation at C3
would be less stabilized than a positive charge at C2, due to the
effect of the lone pair of the nitrogen. The latter would lead to
the C2-regioselective hydroarylation of indoles which is the
subject of this report (Scheme 2).
Scheme 2. Arylative dearomatisation of N-Ac indoles mediated by FeCl3.
Results and discussion
We started with N-Ac indole 7a as the electrophilic indole and
we investigated a broad range of aromatic nucleophiles 5 at
room temperature in dichloromethane in presence of 2.4
equivalents of FeCl3 (Table 1). Anisole 5a reacts selectively at
the C2-position of 7a in a 86% yield with a 1:1 mixture of
addition products from the para and ortho positions of 5a (entry
1). Arenes containing a strong electrondonating group such as
4-methyl anisole 5b, 1,4-dimethoxybenzene 5c, 1,3-
dimethoxybenzene 5d, 4-methylphenol 5e delivered
regioselectively and efficiently the C2-arylated N-Ac indoles 8b-
e in 86-46% yields (entries 2-5).19 Xylenes 5f-h were also good
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a) Isolated yield.
At the 5-position, indoles containing an elecVtrieownAdrtoiclneaOtnilninge
groups such as methoxy and methyl groups reacted efficiently
DOI: 10.1039/C6CC01654E
We then turned our attention to the scope of N-Ac indoles 7
with 4-methylanisole 5b and 1,4-dimethoxybenzene 5c as
nucleophiles (Table 2).
with 5b delivering 8l,n in 67% and 74% yields (entries 1,3). The
reaction between 5-methoxy-N-Ac indole 7b and 5c afforded
moderate yield of 8m (entry 2). The 5-bromo-N-Ac indole
reacted well with 5b,c leading to 8o,p in 83% and 54% yields
(entries 4, 5). Remarkably, a strong electronwithdrawing group
such as a nitro at the 5-position afforded 40% yield of 8q (entry
6). At the 6-postion the chloro derivative 7f delivered 8r,s in
55% and 62% yields with 5b,c (entries 7, 8). Substitution at the
4-position was also tolerated and 4-bromo-arylated indoline 8t
was obtained in 85% yield (entry 9). Finally, indoline 8u,
containing an arylated quaternary carbon, was obtained in 30%
yield from 2-methyl-N-Ac indole 7h (entry 10). In this case, the
hydroarylation reaction is in competition with the migration of
the acetyl from the N-position to the C3-position.
Table 2. Scope of electrophilic indoles 7.
Entry
Indole 7
R3
Product 8
Yielda
In order to obtain more diversified drug-like compounds, we
studied the C2-addition of heterocycles such as
benzothiophene 9a or benzofuran 9b to N-Ac indole 7a (Scheme
3).
Scheme 3. Addition of heterocycles to N-Ac indole.
Surprisingly, along with the expected C2-hydroarylated
compounds 10a,b we also observed as the major products, the
formation of compounds 11a,b.19
Compounds 11a,b most probably raised from to the unexpected
opening of the indole ring of 10a,b with the cleavage of the C2-
NAc bond assisted by the lone-pair of the oxygen or sulfur atom.
The resulting benzylic cationic intermediate could then be
attacked by the addition of a second heteroarene. Such
transformations have been observed during the trimerisation of
indoles in acidic conditions 20
On a final note, we achieved the intramolecular 6-endo-trig
arylation of 12a,b which contain an aryl group on the C3-side
chain of the indole leading to tetracyclic compounds 13a,b
arylated at the C2-position (Scheme 4).19 This is in contrast with
the usual hydroarylation of 3-substituted N-Ac indoles which
proceeds at the C3-position.3
The structures of compounds 8b, 11a and 13b were confirmed
by X-Ray crystallography (Figure 3).19
a) Isolated yield; b) 28% of 3-acetyl-2-methyl-indoles was isolated.
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We have achieved the dearomative C2-arylation of N-Ac indoles
by functionalization of the C-H bond of electron rich arenes at
room temperature, in air with a cheap and non-toxic promotor.
A broad scope of N-Ac indoles and arene nucleophiles is
tolerated. Presumably, the key of this reaction is the generation
of an electrophilic indole by activation of the N-Ac indole with
FeCl3 which triggers a Friedel-Crafts reaction.
The research leading to these results has received funding from
the People Programme (Marie Curie Actions) of the European
Union's Seventh Framework Programme FP7/2007-2013/ under
REA grant agreement n° 623422 (IIF-2013 postdoctoral
fellowship to R.K.N.). We also gratefully acknowledge the ANR
(JCJC program 2012, ANR-12-JS07-0002; “CouPhIn”), the
Université Paris Sud and the CNRS for financial support. The X-
Ray diffractometer was purchased with funds from Région Ile
de France (SESAME program 2012, N°12018501), IUF, LabEx
CHARM3AT, Univ. Paris Sud and CNRS.
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